Flow cytometer system including flow cytometer, autosampler and system integration structure

ABSTRACT

A flow cytometer system includes a flow cytometer, an autosampler and a system integration structure to accommodate interconnection and interface of the flow cytometer and autosampler for operation together and providing for convenient interface with equipment for handling process liquids.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a divisional of U.S. patent application Ser. No.15/127,732 entitled “FLOW CYTOMETER SYSTEM INCLUDING FLOW CYTOMETER,AUTOSAMPLER AND SYSTEM INTEGRATION STRUCTURE” having a 371(c) date ofSep. 20, 2016 further identified as attorney docket no. 50911-00045,which is a U.S. national stage filing under the Patent CooperationTreaty of international patent application no. PCT/US2015/020512 filedMar. 13, 2015 further identified as attorney docket no. 50911-00026,which claims the benefit of U.S. provisional patent application No.61/969,021 entitled “FLOW CYTOMETER SYSTEM INCLUDING FLOW CYTOMETER,AUTOSAMPLER AND SYSTEM INTEGRATION STRUCTURE” filed Mar. 21, 2014further identified as attorney docket no. 50911-00017, the entirecontents of each of which are incorporated herein by reference.

FIELD OF THE INVENTION

The invention relates to flow cytometry, including in relation toequipment and systems.

BACKGROUND OF THE INVENTION

Flow cytometry is an analytical technique used in a number ofapplications to measure physical and/or chemical properties ofbiological or nonbiological particles as they flow in a sample fluid,often an aqueous liquid medium, through an investigation cell. Flowthrough the cell may be investigated by a variety of techniques,including subjecting the flow to electrical, acoustic and/or opticalsignals in measuring and analyzing responses to detect and evaluateparticles in the sample.

In order to increase the number of samples that may be processed, a flowcytometer may be coupled to process sample fluids provided by anautosampler. A number of flow cytometer manufacturers have speciallydesigned autosamplers that connect and interface with their flowcytometer product. Such coordinated design between the flow cytometerand autosampler provides convenience to the user, but may limit thecombinations of different autosamplers and flow cytometers that may beused in combination. Furthermore, some flow cytometers may not beprovided by a manufacturer that also provides an autosampler with acoordinated design, which may limit the utility of the flow cytometersto processing only manually provided sample fluid batches.

Although it may be possible in some circumstances to adapt anautosampler and flow cytometer that do not have a coordinated design tooperate together, such adaptation may often be difficult to achieve andmy result in poor interconnection of system components and/or poor spaceutilization.

SUMMARY OF THE INVENTION

In one aspect, a flow cytometer system is disclosed that includes a flowcytometer, an autosampler and a system integration structure that mayprovide operational interface between the autosampler and the flowcytometer and process liquid containers that may provide process liquidsto or receive process liquids from the flow cytometer and theautosampler. The flow cytometer has a sample inlet for receiving asample fluid for flow cytometry analysis of the sample fluid forparticles within the sample fluid. The autosampler is in fluidcommunication with the sample inlet of the flow cytometer, and theautosampler may be operative to automatically provide a series ofbatches of sample fluid to the flow cytometer for flow cytometryanalysis. The system integration structure includes an upper shelfdisposed above the autosampler and on which the flow cytometer issupported above the autosampler. The system integration structureincludes a container rack that has a plurality of receptacles to receivea corresponding plurality of process liquid containers.

In another aspect, a system integration structure, or unit, isdisclosed, such as may be used in the flow cytometer system of theabove-noted aspect. For example, the system integration structure maybe, or may include any feature or features of, the system integrationstructure of the flow cytometer system.

A number of feature refinements and additional features may beapplicable to the flow cytometer system aspect and/or the systemintegration structure aspect of this disclosure, as further disclosedbelow in the detailed description and with reference to the drawingsand/or as disclosed in the claims presented below. These featurerefinements and additional features may be used individually or in anycombination. As such, each such feature may be, but is not required tobe, used with any other feature or combination with any one or morefeatures of the flow cytometer system aspect and/or the systemintegration structure aspect.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 illustrates an embodiment of a flow cytometer system.

FIG. 2 is a perspective view of a system integration structure shown inthe flow cytometer system embodiment of FIG. 1.

FIG. 3 is another perspective view of the system integration structureshown in FIG. 2.

FIG. 4 is an enlarged view of a portion of the system integrationstructure shown in FIG. 2.

FIG. 5 is a perspective view of the flow cytometer shown in the flowcytometer system embodiment of FIG. 1.

FIG. 6 is a front view of the flow cytometer shown in FIG. 5.

FIG. 7 is another perspective view of the flow cytometer shown in FIG.5.

DETAILED DESCRIPTION

FIG. 1 shows an example implementation of a flow cytometer system 100including a flow cytometer 102, an autosampler 104 and a systemintegration structure 106. More detail on the system integrationstructure 106 is shown in FIGS. 2-4 and more detail on the flowcytometer 102 is shown in FIGS. 5-7. The flow cytometer system 100 andcomponents thereof will now be described with reference to FIGS. 1-7.

The system integration structure 106 includes a lower shelf 108, onwhich is supported the autosampler 104, and an upper shelf 110, on whichis supported the flow cytometer 102. The flow cytometer 102 has a sampleinlet 112 (shown in FIG. 6) that is in fluid communication with theautosampler 104 to receive batches of sample fluid for flow cytometryanalysis in the flow cytometer 102 through a sample feed conduit 114.The sample feed conduit 114 passes through a passage 116 through theupper shelf 110 into an internal passage 118 of a riser 120 of thesystem integration structure 106. The sample inlet 112 is disposed inthe internal passage 118 of the riser 120 to be protected by the wall ofthe riser 120. During operation, the autosampler 104 may automaticallysample batches of sample fluid to be analyzed, such as may be providedin a multi-well sample tray that may be disposed in the autosampler 104through the front access provided by a front door 122 of the autosampler104. The autosampler 104 may also have a side access 124, which as shownin FIG. 1 may be in the form of an access panel that may be removable toprovide access through the side of the autosampler 104, such as formaintenance purposes or to replace reagent bottles that may be disposedwithin the autosampler 104.

During operation of the flow cytometry system 100, various processliquids may be consumed by the autosampler 104 and/or the flow cytometer102 and waste liquids from such processing must be collected. Suchprocess liquids that may be supplied to the autosampler 104 and/or theflow cytometer 102 include, for example, rinse buffer solution, washliquid and sheath liquid. Waste liquids may include process samples andsheath fluid after being subjected to flow cytometry analysis, as wellas used rinse buffer solution and used wash liquid. One or morecontainers for providing these or other process liquids and/orcontainers for receiving waste liquids may be disposed in one or both ofthe autosampler 104 and the flow cytometer 102. However, it may beconvenient to provide one or more liquid containers for such purposeexternal to the flow cytometer 102 and the autosampler 104, permittingsignificant flexibility in accommodating use of a combination of variousflow cytometers and autosamplers not specifically designed andmanufactured to interconnect and interface with each other, such as maybe the case if they were designed and manufactured by a singlemanufacturer.

The system integration structure 106 includes a container rack 126 witha plurality of receptacles 128 configured to receive a correspondingplurality of process liquid containers that may provide a source ofprocess liquid or a vessel to receive used process liquid, such as wasteliquid, from operations involving the flow cytometer 102 and/or theautosampler 104. The flow cytometer system 100 as shown in FIG. 1includes a plurality of process liquid containers 130 a-d received inthe receptacles 128 and with fluid conduits 132 a-d fluidly connectedwith corresponding ones of the process liquid containers 130 a-d. Eachof the fluid conduits 132 is in fluid communication with either the flowcytometer 102 or the autosampler 104, or possibly with both. Thereceptacles 128 may be configured with a cross-section to correspondwith a cross-section of process liquid containers to be received in thereceptacles (e.g., corresponding circular cross-sections). One or evenall of the receptacles 128 may have a different cross-sectionconfiguration from one or more other receptacles 128 to key withdifferent corresponding exterior cross-sectional shapes of differentprocess liquid containers 130.

In the particular implementation shown in the figures, the containerrack 126 is formed as a unitary piece. In alternative implementations,the features of such a container rack 126 may be provided in a pluralityof pieces that provide receptacles 128 to receive a sufficient number ofprocess liquid containers 130 appropriately located in relation to theaccess opening feature 136. For example, one or more of all of thereceptacles 128 may be provided in one rack piece, or in one assembly ofmultiple rack pieces, and one or more other ones of the receptacles 128may be provided in one or more other rack pieces, or assemblies ofmultiple rack pieces. Such different rack pieces or assemblies need notbe contiguous.

Each of the fluid conduits 132 is routed toward the flow cytometer 102or the autosampler 104 through a routing channel that is within a firstsupport member 134 of the system integration structure 106. The routingchannel within the first support member 134 extends through the fulllength of the first support member 134 between the lower shelf 108 andthe upper shelf 110. The fluid conduits 132 are routed into the routingchannel within the first support member 134 through an access openingfeature 136, which is shown in FIGS. 1 and 2, and may be in the form ofone or a plurality of holes passing through a side wall of the firstsupport member 134. As shown in FIG. 1, the access opening feature 136may include holes that are sized to accommodate passage of only a singleone of the fluid conduits 132 through each hole. The access openingfeature 136 is at a vertically elevated position relative to theelevation of the receptacle 128, and relative to the tops of the processliquid containers 130 when received in the receptacles 128. This is thecase whether a fluid conduit 132 will be routed upward through therouting channel in the first support member 134 toward the flowcytometer 102 or will be routed downward through the routing channeltoward the autosampler 104. As seen in FIG. 4, holes 138 of the accessopening feature 136 may be configured to receive a grommet (e.g., arubber grommet) sized to snuggly fit around the fluid conduits 132 tohelp retain the fluid conduits 132 and prevent them from moving aroundover time or during operations to fill or remove liquid from the processliquid containers 130. The access opening feature 136 may include anumber of the holes that is at least equal to the number of receptacles128, or that may even be greater than the number of receptacles 128 toaccommodate multiple fluid conduits 132 to a single process liquidcontainer 130, for example to provide pressurized gas to a processliquid container 130 to provide pressurization to drive liquid out ofthe respective process liquid container 130 to the flow cytometer 102 orthe autosampler 104, as the case may be. In some implementations, thecontainer rack may include four of the receptacles 128 or may include agreater or smaller number of such receptacles 132 to provide locationsfor a greater or smaller number of process liquid containers 130. Forsome implementations, the access opening feature 136 may include atleast six holes for passing the fluid conduits 132, with six to eightholes often being sufficient for accommodating four process liquidcontainers 130. The implementation of the system integration structure106 shown in the figures includes seven such holes.

Although in the particular implementation shown in the figures theaccess opening feature 136 includes a plurality of holes, in alternativeimplementations, the access opening feature may include a single, largeropening through the wall of the first support member 134 through whichall of the fluid conduits 132 a-d may pass together. In otheralternative implementations, the access opening feature 136 may includea plurality of openings through the side wall of the first supportmember 134 with multiple ones of the fluid conduits 132 passing throughone or more of the openings together. And yet in other alternativeimplementations, holes of the access opening feature 136 may be arrangedin a different configuration than the linear configuration shown in thefigures. For example, such a configuration may include any geometricpattern for spacing the holes in a desired manner.

The routing channel through the first support member 134 extends upwardfrom the access opening feature 136 and is open to an opening 140through the upper shelf 110 and through which the fluid conduits 132 maybe routed for fluid connection with the flow cytometer 102. The routingchannel through the first support member 134 extends downward from theaccess opening feature and is open to a space 142 located below thelower shelf 108. Fluid conduits 132 may be routed through the space 142to the side of the lower shelf 108 opposite the first support member 134and may be routed through two routing holes 144 through the lower shelf108 to permit fluid connection of the fluid conduits 132 with theautosampler 104. In some implementations, the lower shelf 108 could beeliminated from the system integration structure 106, and theautosampler 104 could be disposed, for example, directly on the surface,such as a surface of a table or work bench, on which the systemintegration structure 106 is supported. Including the lower shelf 108 ispreferred to provide additional stability to the flow cytometer system100 and to provide the space 142 below the lower shelf 108 for routingfluid conduits 132 to the autosampler 104.

As seen in FIG. 3, the first support member 134 includes an access piece145, shown in the form of an access panel, located on the inside of thefirst support member 134 and which may be removed to permit access tothe routing channel to facilitate easy threading of the fluid conduits132 through the routing channel in the appropriate direction toward theflow cytometer 102 or the autosampler 104. In some implementations, afluid conduit 132 may be branched within the routing channel within thefirst support member 134 into separate fluid conduit branches with onefluid conduit branch connecting with the flow cytometer 102 and anotherfluid conduit branch connecting with the autosampler 104. For example,one fluid conduit branch may receive waste liquid from the flowcytometer 102, while the other fluid conduit branch may receive wasteliquid from the autosampler 104, and both such waste liquids may bedirected to and received within a single process liquid container 130through a single fluid conduit 132 to that process liquid container 130.As shown in FIG. 7, the flow cytometer 102 may include a singlepass-through port 146 through which a bundle of all of the fluidconduits 132 directed to the flow cytometer 102 may be provided to theinterior of the flow cytometer 102 to make the appropriate fluidconnections within the flow cytometer 102.

The system integration structure 106 includes a second support member148 disposed opposite the first support member 134. The first supportmember 134 and the second support member 148 together fully support theupper shelf 110 and the flow cytometer 102. The first support member 134and the second support 148 member define a vertical separation distancebetween the lower shelf 108 and the upper shelf 110 to providesufficient vertical space for receiving the autosampler 104 to bedisposed between the lower shelf 108 and the upper shelf 110. The firstsupport member 134 and the second support member 148 are spacedsufficiently far apart to permit at least a back portion of theautosampler 104 between the first support member 134 and the secondsupport member 148. The routing holes 144 through the bottom shelf 108are located in front of the second support member 148 to provide accessfor routing fluid conduits 132 to a side of the autosampler 104 oppositethe container rack 126. The lower shelf 108 has a front edge 150 towarda front side of the system integration structure 106 and a back edge 152toward a back side of the system integration structure 106. Likewise,the upper shelf 110 includes a front edge 154 toward the front side ofthe system integration structure 106 and a back edge 156 toward the backside of the system integration structure 106. The first support member134 and the second support member 148 are disposed in the rear half ofthe system integration structure 106 to provide for easy access from thefront and sides of the system integration structure 106 to theautosampler 104. The autosampler 104 has a front access in the form ofthe front door 122 that is easily accessible from the front of thesystem integration structure 106. The side access 124 is also easilyaccessible from the side of the system integration structure 106 withoutinterference from the first support member 134, as the first supportmember 134 is not disposed opposite the side access 124. The systemintegration structure 106 is also open to the back to permit easy accessto the back of the autosampler 104. If the autosampler 104 includes sideaccess through the side of the autosampler 104 opposite the side access124, the second support member is preferably not opposite suchadditional side access so that such additional side access is easilyaccessible from the side of the autosampler 104 adjacent the secondsupport member 148.

The upper shelf 110 includes a number of features for accommodating theflow cytometer 102. The upper shelf 110 includes a plurality ofregistration recesses 158, shown in the form of circular recesses in thecenter of disks retained on the top surface of the upper shelf 110. Suchdisks may be, for example, in the form of metal washers attached tosurrounding surfaces of the upper shelf 110. The registration recesses158 are sized and located to correspond with a plurality of feet 160 ofthe flow cytometer 102. The feet 160 are retained in a fixed relation tothe upper shelf 110 by the registration recesses 158 to prevent the flowcytometer 102 from moving laterally on the upper shelf 110 during use,which could for example damage the sample inlet 112 of the flowcytometer 102. In one enhancement, the feet 160 may be made of anelastomeric material to provide motion dampening (e.g., some level ofvibration isolation) to the flow cytometer 102. Likewise, in anotherenhancement, feet 162 (shown in FIG. 1) on which the system integrationstructure 106 is supported may likewise be of an elastomeric materialthat provides additional motion dampening to the system integrationstructure 106 and consequently also to the flow cytometer 102. As willbe appreciated, providing for vibration isolation to the flow cytometer102 may be significantly beneficial in preventing vibrational or othermotions from interfering with flow cytometry analysis.

The upper shelf 108 includes a perimeter liquid containment lip 156 thatcompletely surrounds the perimeter of the flow cytometer 102 andprovides for containment of liquid on the upper shelf 110 in the eventthat liquid should spill or otherwise collect on the upper shelf 110.The liquid containment lip 156 may have a height for fluid containmentof at least 1 centimeter, at least 2 centimeters, at least 3centimeters, at least 4 centimeters, at least 5 centimeters or more, andmay in some implementations be not larger than 10 centimeters or evennot larger than 5 centimeters in height, to provide significant fluidcontainment capacity while still providing for relatively easy access tothe flow cytometer 102.

In some implementations, not shown in the figures, one or more of theprocess liquid containers 130 may have multiple fluid conduits 132fluidly connected with the process liquid container 130. For example, insome implementations process liquid may be caused to flow from a processliquid container 130 to the flow cytometer 102 and/or to the autosampler104 by pressurized gas (e.g., pressurized air, nitrogen or other gas)applied through one of the fluid conduits 132 to force flow of processliquid from the process liquid container 130 through another one of thefluid conduits 132 connected with the process liquid container 130. Sucha gas fluid conduit 132 may be in fluid communication with a source ofcompressed gas to pressurize the process liquid container. In oneenhancement, such a gas fluid conduit 132 to a process liquid container130 may be fluidly connected with the source of compressed gas throughthe flow cytometer 102, which may control the delivery of pressurizedgas through the gas fluid conduit 132 to the corresponding processliquid container 130. Such a gas fluid conduit 132 may be routed throughthe routing channel through the first support member 134 to a connectionin the flow cytometer 102 for supply of compressed gas through the gasfluid conduit 132. As shown in FIG. 7, the flow cytometer 102 mayinclude a gas line connector 164 which may be fluidly connected with apressurized gas source, such as pressurized gas in a bottle or acompressed gas delivery system within a facility. Multiple ones of suchprocess liquid containers 130 may each be connected with multiple suchfluid conduits 132, with one providing pressurized gas to drive liquidflow from the process liquid container 130. One process liquid that maybe contained within one of the process liquid containers 130 may be asheath fluid, typically an aqueous liquid, that may be used in the flowcytometer 102 to hydrodynamically focus sample fluids for flow cytometryanalysis by the flow cytometer 102. Flow of such a sheath fluid, forexample, may be driven by pressurized gas delivered to a process liquidcontainer 130 in such a manner.

The foregoing discussion of the invention and different aspects thereofhas been presented for purposes of illustration and description. Theforegoing is not intended to limit the invention to only the form orforms specifically disclosed herein. Consequently, variations andmodifications commensurate with the above teachings, and the skill orknowledge of the relevant art, are within the scope of the presentinvention. The embodiments described hereinabove are further intended toexplain best modes known for practicing the invention and to enableothers skilled in the art to utilize the invention in such, or other,embodiments and with various modifications required by the particularapplications or uses of the present invention. It is intended that theappended claims be construed to include alternative embodiments to theextent permitted by the prior art. Although the description of theinvention has included description of one or more possible embodimentsand certain variations and modifications, other variations andmodifications are within the scope of the invention, e.g., as may bewithin the skill and knowledge of those in the art after understandingthe present disclosure. It is intended to obtain rights which includealternative embodiments to the extent permitted, including alternate,interchangeable and/or equivalent structures, functions, ranges or stepsto those claimed, whether or not such alternate, interchangeable and/orequivalent structures, functions, ranges or steps are disclosed herein,and without intending to publicly dedicate any patentable subjectmatter. Furthermore, any feature described or claimed with respect toany disclosed variation may be combined in any combination with one ormore of any other features of any other variation or variations, to theextent that the features are not necessarily technically compatible, andall such combinations are within the scope of the present invention. Thedescription of a feature or features in a particular combination do notexclude the inclusion of an additional feature or features. Processingsteps and sequencing are for illustration only, and such illustrationsdo not exclude inclusion of other steps or other sequencing of steps.Additional steps may be included between illustrated processing steps orbefore or after any illustrated processing step.

The terms “comprising”, “containing”, “including” and “having”, andgrammatical variations of those terms, are intended to be inclusive andnonlimiting in that the use of such terms indicates the presence of somecondition or feature, but not to the exclusion of the presence also ofany other condition or feature. The use of the terms “comprising”,“containing”, “including” and “having”, and grammatical variations ofthose terms in referring to the presence of one or more components,subcomponents or materials, also include and is intended to disclose themore specific embodiments in which the term “comprising”, “containing”,“including” or “having” (or the variation of such term) as the case maybe, is replaced by any of the narrower terms “consisting essentially of”or “consisting of” or “consisting of only” (or the appropriategrammatical variation of such narrower terms). For example, a statementthat something “comprises” a stated element or elements is also intendedto include and disclose the more specific narrower embodiments of thething “consisting essentially of” the stated element or elements, andthe thing “consisting of” the stated element or elements. Examples ofvarious features have been provided for purposes of illustration, andthe terms “example”, “for example” and the like indicate illustrativeexamples that are not limiting and are not to be construed orinterpreted as limiting a feature or features to any particular example.The term “at least” followed by a number (e.g., “at least one”) meansthat number or more than that number. The term at “at least a portion”means all or a portion that is less than all. The term “at least a part”means all or a part that is less than all.

1-4. (canceled)
 5. A flow cytometer system, comprising: a flow cytometerwith a sample inlet for receiving a sample fluid for flow cytometryanalysis of the sample fluid for particles within the sample fluid; anautosampler in fluid communication with the sample inlet of the flowcytometer and operative to automatically provide a series of batches ofsample fluid to the flow cytometer for flow cytometry analysis; a systemintegration structure, comprising: an upper shelf disposed above theautosampler and on which the flow cytometer is supported above theautosampler; a container rack comprising a plurality of containerreceptacles to receive a corresponding plurality of process liquidcontainers to provide a source of process liquid to and receive usedprocess liquid from operations of the flow cytometer and autosampler;and a routing channel to route fluid conduits from process liquidcontainers toward the flow cytometer and the autosampler when the liquidcontainers are received in the container rack; wherein the at least oneaccess opening includes a plurality of holes through the side wall ofthe support member.
 6. A flow cytometer according to claim 5, whereinthe plurality of holes includes a number of the holes that is at leastequal to a number of the receptacles of the container rack.
 7. A flowcytometer system according to claim 6, wherein the container rackincludes at least four of the receptacles and the at least one openingincludes at least six of the holes.
 8. A flow cytometer according toclaim 5, wherein: the routing channel extends from the at least oneaccess opening in a upward direction through the support member forrouting of one or more of the fluid conduits to the flow cytometerlocated at a higher elevation than the at least one opening; and therouting channel extends from the at least one access opening in adownward direction through the support member for routing one or more ofthe fluid conduits to the autosampler.
 9. The flow cytometer systemaccording to claim 8, wherein the routing channel is open to an openingthrough the upper shelf that provides for routing one or more of thefluid conduits from the routing channel below the upper shelf to theflow cytometer.
 10. The flow cytometer system according to claim 8,wherein: the system integration structure comprises a lower shelf onwhich is supported the autosampler; and the routing channel extendsdownward to a space located below the lower shelf for routing one ormore of the fluid conduits under the lower shelf directed to theautosampler.
 11. A flow cytometer system according to claim 10, whereinthe support member extends from the lower shelf to the upper shelf. 12.A flow cytometer system according to claim 10, wherein: the supportmember is a first support member and the system integration structurecomprises a second support member; and wherein at least a portion of theautosampler is disposed on the lower shelf between the first supportmember and the second support member.
 13. A flow cytometer systemaccording to claim 12, wherein the lower shelf has a front edge and aback edge; the autosampler has a side access between the front edge andthe back edge of the lower shelf; and neither the first support membernor the second support member is disposed opposite the side access. 14.A flow cytometer system according to claim 13, the autosampler has afront and a back corresponding to front and a back of the systemintegration structure and the system integration structure is open tothe front and the back between the first and second support members toprovide access to the front and the back of the autosampler. 15-40.(canceled)